ATP-phosphoribosyltransferase catalyses the first committed step of histidine biosynthesis in archaea, bacteria, fungi and plants. There are two families of this enzyme, the long form (HisG_L) and the short form (HisG_S).  While the two families share characteristic structural features and carry out the same biochemical function, they differ in their overall molecular architecture and mode of allosteric regulation.

The monomeric unit of the long form (HisG_L) consists of three domains, two of which comprise the active site of the enzyme while the third is a regulatory domain that forms the allosteric binding site for the inhibitor, histidine. The crystal structure of HisG_L reveals a homo-hexameric quaternary structure.¹

The short form is structurally similar to the catalytic domain of HisG_L but is missing the regulatory domain. This protein instead forms a non-covalent complex with another protein, HisZ, which provides the allosteric binding site for histidine.²

Previous research has suggested that HisG_S is not catalytically competent in the absence of HisZ, despite housing the catalytic machinery of the enzyme.³ Recent work in our laboratory has revealed the ability of a modified HisG_L to function independently of its regulatory domain. The purpose of this research is to understand the structure and function of the short form enzyme and the evolutionary relationship between the two families.